Gd(iii)-Pt(iv) theranostic contrast agents for tandem MR imaging and chemotherapy.

Casey J Adams,Thomas J Meade

doi:10.1039/c9sc05937g

Abstract

Pt(iv) prodrugs have emerged as versatile therapeutics for addressing issues regarding off-target toxicity and the chemoresistance of classic Pt(ii) drugs such as cisplatin and carboplatin. There is significant potential for Pt(iv) complexes to be used as theranostic agents, yet there are currently no reported examples of Gd(iii)–Pt(iv) agents for simultaneous MR imaging and chemotherapy. Here we report the synthesis, characterization, and in vitro efficacy of two Gd(iii)–Pt(iv) agents, GP1 and GP2. Both agents are water soluble and stable under extracellularly relevant conditions but are reduced under intracellular conditions. Both are cytotoxic in multiple cancer cell lines, cell permeable, and significantly enhance the T1-weighted MR contrast of multiple cell lines. Thus, GP1 and GP2 are promising agents for tandem MR imaging and chemotherapy and provide a versatile platform through which future Gd(iii)–Pt(iv) agents can be developed.

Highlights

Pt(II) chemotherapeutics have been fundamental tools for the treatment of solid tumors.[1,2,3] there have been extensive efforts to develop new Pt-based chemotherapeutics, there are currently only three approved by the FDA: cisplatin, carboplatin, and oxaliplatin.[4,5,6,7] All FDA approved Pt chemotherapeutics are Pt(II) square planar complexes that cross-link DNA, leading to apoptosis in fast-dividing cells.[1,8] This mechanism of action makes them highly effective at treating solid tumors
Pt(IV) prodrugs have emerged as versatile therapeutics for addressing issues regarding off-target toxicity and the chemoresistance of classic Pt(II) drugs such as cisplatin and carboplatin
We report the synthesis, characterization, and in vitro efficacy of two Gd(III)–Pt(IV) agents, GP1 and GP2. Both agents are water soluble and stable under extracellularly relevant conditions but are reduced under intracellular conditions. Both are cytotoxic in multiple cancer cell lines, cell permeable, and significantly enhance the T1-weighted MR contrast of multiple cell lines

Summary

Introduction

Pt(II) chemotherapeutics have been fundamental tools for the treatment of solid tumors.[1,2,3] there have been extensive efforts to develop new Pt-based chemotherapeutics, there are currently only three approved by the FDA: cisplatin, carboplatin, and oxaliplatin.[4,5,6,7] All FDA approved Pt chemotherapeutics are Pt(II) square planar complexes that cross-link DNA, leading to apoptosis in fast-dividing cells.[1,8] This mechanism of action makes them highly effective at treating solid tumors. These agents are water soluble, cell permeable, and oxidatively stable, but are reduced under biologically relevant intracellular conditions to release the toxic Pt(II) payload and the Gd(III) MR agent (Scheme 1). Intracellular contrast enhancement of cancer cells, whereas typical Gd(III) contrast agents are limited to the extracellular space surrounding tumors.[34,40] This Gd(III)–Pt(IV) platform possesses a second axial site that can be used to couple targeting groups for tumor speci city, drugs to combat chemoresistance, or uorophores for multimodal imaging and validation.

Results

Conclusion